Genotypephenotype Correlation

The myocardium is a heterogeneous milieu with multiple cellular subtypes having different functional and electrophysiological properties.1-4-1 These electrophysiological distinctions are due to variations in the expression of ionic currents, especially between epicardium and endocardium. These differences contribute to the development of ST segment elevation and the substrate for reentrant arrhythmias. Experiments involving the arterially perfused right ventricular wedge preparation have shown the epicardial action potential notch is responsible for inscription of the electrocardiographic J wave and accentuation of the notch leads to amplification of the J wave, resulting in an apparent elevation of the ST segment.[5] This has been shown in pathophysiological states such as hypothermia, where an increase in the notch in the epicardium, but not the endocardium, causes an elevation of the J point and ST segment in the electrocardiogram. If the epicardial action potential repolarizes before that of the endocardium, the T wave will remain positive and the electrocardiogram will show a saddleback type of ST segment elevation. Further accentuation of the pathophysiological state will accentuate the notch and prolong the epicardial action potential so that it repolarizes after the endocardial response, thus leading to inversion of the T wave. The result is an electrocardiogram with a coved ST segment elevation and a negative T wave as observed in Brugada syndrome shown in Fig. 1. Progressive accentuation of the notch will eventually lead to loss of the action potential dome and marked abbreviation of the epicardial response.[6] The end result will be the creation of a transmural gradient between epicardium and endocardium, and thus the substrate for reentrant arrhythmias.[7] This is the mechanism believed to induce ventricular arrhythmias and sudden death.

Experimental models of the Brugada syndrome created by exposing right ventricular wedge preparations to a variety of pharmacological agents have highlighted the importance of Ito. The high expression of Ito during phase 1 of the action potential plays a pivotal role in the electrocardiographic pattern of the Brugada syndrome. It is the balance of currents active during phase 1 that determines the degree of ST segment elevation. The use of quinidine, a class IA antiarrhythmic with action to block Ito, among other currents, has been shown to be capable of restoring the action potential dome in epicardium, thus normalizing the ST segment elevation.[6] It is certainly a finding which could have clinical and therapeutic relevance. There is a group who advocate the use of this antiarrhythmic to treat Brugada syndrome[8] and there has been a case report in the literature of decreased ST elevation with the use of quinidine.[9]

Sodium channel blockers also increase the notch of the epicardial action potential and thus give rise to an ST segment elevation in the wedge preparation.1-6-1 This has also proved useful in clinical practice as a form of diagnostic tool to unmask the electrocardiographic pattern in individuals suspected of having the Brugada syndrome. Sodium blockers such as ajmaline, procainamide, flecai-nide, and pilsicainide are now being used as diagnostic test to identify individuals with concealed Brugada syndrome.[10]

Two intriguing questions have arisen in recent years. One is why is this electrocardiographic pattern only present in the right precordial leads, and the second is why the Brugada phenotype is so much more prevalent in males vs. females of Southeast Asian origin. In the experimental myocardial, Ito is much more prominent in males than in females[11] and is much greater in the right ventricle than in the left ventricle of the heart.[12]

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